WO1999001462A1 - Multinuclear cationic platinum complexes with antitumor activity - Google Patents

Multinuclear cationic platinum complexes with antitumor activity Download PDF

Info

Publication number
WO1999001462A1
WO1999001462A1 PCT/EP1998/004057 EP9804057W WO9901462A1 WO 1999001462 A1 WO1999001462 A1 WO 1999001462A1 EP 9804057 W EP9804057 W EP 9804057W WO 9901462 A1 WO9901462 A1 WO 9901462A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
alkyl
integer
Prior art date
Application number
PCT/EP1998/004057
Other languages
English (en)
French (fr)
Inventor
Giovanni Da Re
Roberto Di Domenico
Silvano Spinelli
Nicholas Farrell
Original Assignee
F. Hoffman-La Roche Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F. Hoffman-La Roche Ag filed Critical F. Hoffman-La Roche Ag
Priority to US09/446,867 priority Critical patent/US6313333B1/en
Priority to AU88050/98A priority patent/AU8805098A/en
Publication of WO1999001462A1 publication Critical patent/WO1999001462A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the present invention relates to tetra- and penta- nuclear platinum complexes with antitumor activity, to a method for preparing them and to pharmaceutical compositions containing them. STATE OF THE ART
  • platinum complexes in the antitumor chemotherapy are well known.
  • a number of platinum complexes, such as ci ⁇ -platin are used in the treatment of testicular, ovarian, head and neck and small cell lung carcinomas.
  • the treatment with cis-platin may result in severe nephrotoxicity.
  • a further clinical disadvantage is the problem of acquired drug resistance resulting in the tumor becoming refractory to treatment by the agent. it is generally believed that platinum complexes such as cis-platin manifest their biological activity through covalent interaction with DNA.
  • cis-platin induces the formation of a range of adducts on DNA including monodentate adducts, bidentate adducts, such as GG or AG, and GNG intrastrand crosslinks [Reedijk et al., Structure and Bonding, 67, 53-89 (1987)].
  • cis-platin also results in interstrand GG crosslinks and DNA-protein crosslinks [Rahmouni et al . , Biochemistry, 26, 7229-7234 (1987)].
  • These DNA lesions result in conformational changes which are reflected in bending and local unwinding of the DNA.
  • Mono (platinum) and bis(platinum) complexes containing respectively one or two platinum atoms, are compounds known in the art (U.S. Patent No. 4,225,529, 4,250,189, 4,533,502, 4,565,884, 4,571,335 e 4,797,393).
  • Examples of tri-nuclear platinum complexes also named tri-platinum complexes
  • Said compounds, in which the ligands have a cis configuration are complexes neutral or bearing an overall charge of +2 and they can be represented by the following general formulae:
  • Such compounds have an overall charge of +4 and in particular the central platinum atom bears a formal charge of +2 and the two periferal platinum atoms bear a formal charge of +1 each. Moreover, the two periferal platinum atoms are monofunctional .
  • the invention relates to tetra- and penta-platinum complexes of formula (I):
  • n is an integer from 2 to 7;
  • m is the integer 2 or 3;
  • X is selected in the group consisting of chlorine, bromine, iodine, (C -C 4 )alkyl-carboxylate , di-(C 1 -C 4 )al- kylsulfoxide; is independently selected in the group consisting of ammonia, (C ⁇ -Cg )alkyl-amine , di (C- ⁇ -Cg )alkyl-amine or is an heterocylcle selected in the group consisting in pyridine, quinoline, isoquinoline , imidazole, thiazole, pyrimidine, purine, acridine, pyrazole, benzimidazole , benzothiazole .
  • a ⁇ z is a pharmaceutically accetable anion.
  • ligands may be in cis or trans position with respect to the platinum atom:
  • n is an integer which independently ranges from 2 to 7 and q' is 0 if X is a ligand with -1 charge or the integer 2 if X is a neutral ligand.
  • the X ligands are preferably selected in the group consisting of chlorine, bromine and iodine.
  • the ligands L are preferably ammonia.
  • a ⁇ z is preferably selected in the group consisting of chloride, bromide, iodide, nitrate. sulfate, hydrogensulfate, perchlorate.
  • Tetra- and penta-platinum complexes having the same n value inside the molecule, that is in which the various platinum cores are linked by the same diamine, are preferred.
  • Preferred compounds of formula (I) are those in which the ligands are in position trans with respect to the platinum atom.
  • Particularly preferred compounds of formula (I) are those in which X is selected in the group consisting of chlorine, bromine and iodine, L is ammonia and A -2 is selected in the group consisting of chloride, bromide, iodide, nitrate, sulfate, hydrogensulfate , perchlorate and in which the stereochemistry of platinum core's ligands is trans.
  • the present invention encompasses also methods for obtaining the compounds of formula (I).
  • the compounds of formula (II) are known and can be prepared according to the method described in WO 91/03482, which encompasses the reaction of two equivalents of trans- or cis-platinu with a ⁇ ,u- alkanediamine in water overnight.
  • the compounds of formula (Va) can be prepared from the known platinum complexes of formula [PtClXL2] according to the method described in WO 95/26968.
  • the compounds of formula (lb) can be prepared according to scheme 2.
  • Such a synthesis scheme comprises the following steps: (e) activation of the intermediate of formula (VI) through exchange of one chlorine atom with a molecule of dimethylformamide and subsequent reaction of the intermediate so obtained with one equivalent of intermediate of formula (Via), to give the complex of formula (VII); (f) removal of the aminic protecting group from the complex of formula (VII) and subsequent exchange reaction of the counterion so obtained with nitrate ion, obtaining the intermediate of formula (VIII); (g) reaction of two equivalents of intermediate (VIII) with one equivalent of platinum complex of formula (Villa) to give a compound of formula (lb);
  • the compounds of formula (VI) can be prepared from the known platinum complexes of formula [PtC12L2] according to the method described in WO 95/26968.
  • the compounds of formula (Via) can be prepared from the corresponding compounds of formula (VI) by removal of the aminic protecting group. The reaction scheme is the same if X is different from chlorine. In this latter case the starting complex will be [PtClX 2].
  • the compounds of formula (Villa) can be prepared starting from the known platinum complexes of formula [PtC12L2] as described in WO 95/26968.
  • reaction conditions for its removal are those which encompass the use of inorganic acids (for example, hydrochloric acid) or organic acids (for example, trifluoroacetic acid), optionally in water medium.
  • inorganic acids for example, hydrochloric acid
  • organic acids for example, trifluoroacetic acid
  • Preferred conditions are those which encompass the use of hydrogen chloride in alcoholic solution.
  • Activation reaction of the platinum complexes with dimethylformamide and subsequent reaction for the formation of Pt-N bonds are performed according to the methods described in WO 95/26968.
  • preferred conditions for the activation reaction are those which encompass the use of dimethylformamide as the solvent and slight excess of silver nitrate with respect to the platinum complex equivalents, at temperatures ranging from room temperature to 40 °C.
  • Preferred conditions for the reaction of formation of the Pt-N bond are those which encompass the use of a dipolar aprotic solvent such as dimethylformamide and at temperatures ranging from -20°C to 50"C.
  • the intermediate (X) is then submitted, if necessary, to an exchange reaction of the anion A ⁇ z with nitrate anion and finally it is reacted with two equivalents of intermediate of formula (Va), to give the compounds of formula (lb).
  • the intermediate of formula (IX), if L is ammonia, is known or in any case can be prepared as described in WO 95/26968.
  • the compounds of the invention are endowed not only with a high antitumor activity, but also with a low toxicity and therefore their therapeutic index is particularly favourable.
  • the compounds of the invention were evaluated "in vitro" for their cytotoxix effect on various tumor cell lines, among which L-1210, A2780 or L-1210 and A2780 re ⁇ istent to cis-platin.
  • Table I show ⁇ a comparison data between one compound of the invention and ⁇ ome prior art compounds .
  • Table I - "in vitro" cytotoxic activity against murine leukemia L1210
  • the platinum complexes of the present invention resulted particularly active when administered in association with other platinum complexes, showing synergic effect with them.
  • the effective dosage of the compounds of the invention can be determined by an expert clinician with known and conventional methods.
  • the correlation between the dosages used with animals of various species and size and with the human (on the base of mg/m2 of body area) is described in Freirech, E.J. et al.,
  • 1200 g/kg will be administered to the patient, with a dosage regimen which will vary depending on several factors well known to the clinician expert in the art.
  • the platinum complex of the present invention may be administered along with reduced glutathione, as described in GB 2174905 and U.S. 4,871,528.
  • the tumors in the patients which can be treated with the platinum complexes of the present invention are those tumors which are known to be susceptible to cis- platin therapy.
  • the complexes of the present invention are also active against certain tumor resistant to cis- platin.
  • the compounds of the invention can be used for the treatment of the same pathologies for which cis-platin is used. This includes the treatment of tumors, sen ⁇ itization or enhancement of radiation [Douple et al., Cisplatin Current Status and Developments, Ed. A.W.
  • the regimen of treatment can be suitably varied as it is well known to the clinician expert in the treatmet of the tumor forms, depending on the kind of the tumor to be treated and on the conditions of the patient.
  • the compounds of the invention are preferably administered as ⁇ terile aqueous solutions.
  • the solution are preferably administered via endovenous or intra- arterial route, although other administration forms may be suitable in particular cases.
  • the pharmaceutical forms which can be used for parenteral administration encompass sterile aqueous ⁇ olutions or sterile powders for the extemporaneous preparation of the solutions, as well as oily preparations for intramuscular or intraperitoneal administration.
  • Suitable pharmaceutical forms can be syrups or similar liquid forms, as well as solid forms such as tablets, capsules or the like.
  • N-BOC hexanediamine is prepared starting from its hydrochloride salt, which is a commercial product. 2.1 g of N-BOC hexanediamine hydrochloride are dissolved in ethyl ether (20 ml) and treated under stirring with 16 ml of a 1 N sodium hydroxide aqueous ⁇ olution.
  • the solid so obtained is dis ⁇ olved in 180 ml of methanol and added with a ⁇ olution of ⁇ ilver nitrate
  • a white ⁇ olid separates which is filtered, redis ⁇ olved in methanol and filtered through a 0.2 micron Millex filter to remove the trace ⁇ of ⁇ ilver ⁇ alt ⁇ .
  • the methanolic ⁇ olution i ⁇ then diluted with ethyl ether.
  • a white ⁇ olid cry ⁇ tallize ⁇ which is filtered and dried, obtaining 1.94 g of the product.
  • the ⁇ olid is filtered, washed on the filter with the mother liquors and then with ethyl ether and finally it is dried in an oven at 40°C overnight. 62 mg of the product are obtained.
  • tran ⁇ -platin ⁇ u ⁇ pended in 5.8 ml of anhydrous dimethylformamide and are added with 69.1 mg of silver nitrate.
  • the reaction mixture is kept under stirring in the darknes ⁇ and at 65°C for 6 hour ⁇ , then it is cooled to room temperature and the precipitated ⁇ ilver chloride i ⁇ removed by filtration. The clear ⁇ olution i ⁇ used as such in the subsequent reaction.
  • PREPARATION 10 Synthesi ⁇ of tran ⁇ -[NH 3 -(CH 2 ) g -NH 2 -Pt (NH 3 ) 2 H 2 N- ( CH 2 ) 5 - NH 3 ] 4+ 4N0 3 - To a ⁇ olution of 12 g of trans- [NH 3 - (CH 2 ) g -NH 2 -
  • the solid so obtained is suspended in 6.5 ml of distilled water, added with 509 mg of ⁇ ilver nitrate and kept under ⁇ tirring in the darkne ⁇ for 30 minutes.
  • the reaction mixture is then filtered, the filtrate is evaporated under reduced pressure and the residue i ⁇ diluted with acetone and kept under stirring overnight.
  • By filtration 470 mg of yellow crystal are separated, which is redissolved in 12 ml of methanol and added with 4 ml of 8 N hydrogen chloride ⁇ olution in ethanol. After ⁇ tirring overnight, the obtained solid is filtered, dried and suspended again in distilled water.
  • the clear filtrate ⁇ o obtained l ⁇ added with about 240 ml of concentrated hydrochloric acid and after 1 hour under stirring at about 5°C the white crystal l ⁇ ⁇ eparated by filtration.
  • the cry ⁇ tal is washed on the filter with 0.1 N hydrochloric acid and then with acetone, then, after purifying it by silica gel chromatography and drying it under vacuum, 190 mg of the product are obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/EP1998/004057 1997-07-04 1998-07-01 Multinuclear cationic platinum complexes with antitumor activity WO1999001462A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/446,867 US6313333B1 (en) 1997-07-04 1998-07-01 Multinuclear cationic platinum complexes with antitumor activity
AU88050/98A AU8805098A (en) 1997-07-04 1998-07-01 Multinuclear cationic platinum complexes with antitumor activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI97A001594 1997-07-04
IT97MI001594A IT1292481B1 (it) 1997-07-04 1997-07-04 Platino complessi cationici tetra- e penta-nucleari ad attivita' antitumorale

Publications (1)

Publication Number Publication Date
WO1999001462A1 true WO1999001462A1 (en) 1999-01-14

Family

ID=11377499

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/004057 WO1999001462A1 (en) 1997-07-04 1998-07-01 Multinuclear cationic platinum complexes with antitumor activity

Country Status (4)

Country Link
US (1) US6313333B1 (xx)
AU (1) AU8805098A (xx)
IT (1) IT1292481B1 (xx)
WO (1) WO1999001462A1 (xx)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010087976A2 (en) * 2009-01-31 2010-08-05 Igf Oncology, Llc Anti-cancer protein-platinum conjugates
CN108727434A (zh) * 2018-07-05 2018-11-02 桂林医学院 11-三氟甲基苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN108752384A (zh) * 2018-07-05 2018-11-06 桂林医学院 苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN109021021A (zh) * 2018-07-05 2018-12-18 桂林医学院 11,12-二氯苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI991508A1 (it) * 1999-07-09 2001-01-09 Novuspharma Spa Nitrati di bis-platino complessi con ligandi poliamminici
US7138520B2 (en) * 2003-01-13 2006-11-21 Massachusetts Institute Of Technology Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same
US8895610B1 (en) 2007-05-18 2014-11-25 Heldi Kay Platinum (IV) compounds targeting zinc finger domains
FR2936357B1 (fr) * 2008-09-24 2010-12-10 Commissariat Energie Atomique Procede de report de puces sur un substrat.
JP5712133B2 (ja) 2008-10-24 2015-05-07 ウェイク フォレスト ユニバーシティ 白金アクリジン抗癌化合物とその製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026968A1 (en) * 1994-03-31 1995-10-12 Boehringer Mannheim Italia S.P.A. Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them
WO1996016068A1 (en) * 1994-11-24 1996-05-30 Boehringer Mannheim Italia S.P.A. Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310047B1 (en) 1999-08-24 2001-10-30 Virginia Commonwealth University High affinity DNA binding compounds as adjuvants in antisense technology

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026968A1 (en) * 1994-03-31 1995-10-12 Boehringer Mannheim Italia S.P.A. Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them
WO1996016068A1 (en) * 1994-11-24 1996-05-30 Boehringer Mannheim Italia S.P.A. Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 127, no. 12, 22 September 1997, Columbus, Ohio, US; abstract no. 170597, RAUTER, HOLGER ET AL: "Selective Platination of Biologically Relevant Polyamines. Linear Coordinating Spermidine and Spermine as Amplifying Linkers in Dinuclear Platinum Complexes" XP002056581 *
INORG. CHEM. (1997), 36(18), 3919-3927 CODEN: INOCAJ;ISSN: 0020-1669, 1997 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010087976A2 (en) * 2009-01-31 2010-08-05 Igf Oncology, Llc Anti-cancer protein-platinum conjugates
WO2010087976A3 (en) * 2009-01-31 2011-02-17 Igf Oncology, Llc Anti-cancer protein-platinum conjugates
JP2012516330A (ja) * 2009-01-31 2012-07-19 アイジーエフ オンコロジー エルエルシー 抗癌タンパク質−白金コンジュゲート
CN108727434A (zh) * 2018-07-05 2018-11-02 桂林医学院 11-三氟甲基苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN108752384A (zh) * 2018-07-05 2018-11-06 桂林医学院 苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN109021021A (zh) * 2018-07-05 2018-12-18 桂林医学院 11,12-二氯苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN108727434B (zh) * 2018-07-05 2020-09-25 桂林医学院 11-三氟甲基苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN109021021B (zh) * 2018-07-05 2020-09-25 桂林医学院 11,12-二氯苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用
CN108752384B (zh) * 2018-07-05 2020-09-29 桂林医学院 苯并咪唑-1,8-萘酰亚胺-铂配合物及其制备方法和应用

Also Published As

Publication number Publication date
AU8805098A (en) 1999-01-25
US6313333B1 (en) 2001-11-06
IT1292481B1 (it) 1999-02-08
ITMI971594A0 (xx) 1997-07-04
ITMI971594A1 (it) 1999-01-04

Similar Documents

Publication Publication Date Title
DK174981B1 (da) 1,2-Bis(aminomethyl)cyclobutan-platin-komplekser, fremgangsmåde til fremstilling heraf, lægemiddel indeholdende samme og fremgangsmåde til fremstilling af et lægemiddel samt anvendelse af komplekserne
JP5052420B2 (ja) 抗腫瘍剤としてのポリアミン配位子を有する新規ビス−プラチナ錯体
EP0753000B1 (en) Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them
US5409915A (en) Bis-platinum (IV) complexes as chemotherapeutic agents
WO1999001462A1 (en) Multinuclear cationic platinum complexes with antitumor activity
JP4167301B2 (ja) 抗腫瘍活性を有するポリメチレン誘導体をリガンドとする新規ビス―プラチナ複合体
EP0793667B1 (en) Trinuclear cationic platinum complexes having antitumour activity and pharmaceutical compositions containing them
HU193339B (en) Process for producing amino-anthracene-dion-platinum-complexes
JP2003506332A (ja) 経口投与活性のあるビス白金錯体
EP1194438B1 (en) Nitrates of bis-platinum complexes with polyamine
US7579373B2 (en) Targeted bisplatinum polyamines as pro-drugs: selective release of platinum
ZA200107313B (en) Water soluble transplatinum complexes with anti-cancer activity and method of using same.
MXPA96004390A (es) Complejos de platino cationico trinucleares conactividad antitumoral y composicionesfarmaceuticas que los contienen
AU2002331665A1 (en) Targeted bisplatinum polyamines as pro-drugs: selective release of platinum

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: KR

WWE Wipo information: entry into national phase

Ref document number: 09446867

Country of ref document: US

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA